DESCRIPTION (Taken from the Investigator's Abstract) Exposure to environmental chemicals may pose hazards to human health, including carcinogenesis. Exposures are more likely to chemical mixtures, especially near hazardous waste sites. Polychlorinated biphenyis (PCBS) and arsenic are two common contaminants which can be found together in mixtures. PCBs are divided into two classes. Coplanar congeners, such as PCB 126, have dioxin(TCDD)-like activity, and nonplanar congeners such as PCB 153 have phenobarbital-like activity. Both have been shown to promote hepatic neoplasia. Coplanar and nonplanar PCBs are likely to be found together in complex mixtures and the combination can act antagonistically on hepatic preneoplastic focus formation in promotion assays. Arsenic, a clastogen thought to influence carcinogenesis at the level of progression, also inhibits pre-neoplastic focus formation. The interaction between PCBs 126 and 153 will be evaluated using a 26-week in vivo initiation/promotion/progression (IPP) assay in the rat using dimethylnitrosamine (DEN) initiation, partial hepatectomy, and subchronic PCB mixture treatment. Promotion and progression will be quantified using glutathione-S-transferase (GST-P) and TGF-alpha positive hepatic foci, respectively. Later studies will incorporate arsenic into the mixture. The role of TGF-beta in cell proliferation and apoptosis will also be evaluated. An in vivo/in vitro IPP assay will be developed using hepatocytes harvested from DEN-initiated rats. Cultured cells will be exposed to mixtures of both PCB congeners as well as arsenic to evaluate interactions between the compounds using assays similar to the in vivo experiments. Results will be compared to the in vivo model in order to validate the cell culture technique as an inexpensive and efficient alternative for evaluating carcinogenesis. Data will be used in a quantitative risk assessment model for PCB and arsenic mixtures. The candidate on this project is Jon Todd Painter, DVM. Dr. Painter's goals are to prepare for a research career combining his training in toxicologic pathology and molecular carcinogenesis. Dr. Painter will have completed his residency training in anatomic pathology and will spend at least 90% of his time on this research at the Center for Environmental Toxicology and Technology at Colorado State University. He will be mentored by a Faculty Committee with research expertise in toxicology, pathology, molecular biology, cell culture, and carcinogenesis.